1. Field of the Invention
The instant invention is a novel method for treating tumors with a toxin. More specifically, the present method involves preliminarily immunizing a patient with a toxin vaccine containing a cytotoxic cancerostatic toxin or toxin surrogate to generate an immune response to the toxin in the patient and to thereby provide systemic protection from the toxin in the patient, and then administering the cytotoxic cancerostatic toxin to the patient to directly treat the tumor.
2. Description of Related Art
Various methods for treating tumors using toxins have been known and are presently under investigation. The most common of these methods is immunotoxin therapy, which involves administering to a cancer patient usually by systemic infusion a toxin linked to a peptide ligand. The ligand portion of the immunotoxin is usually an antibody or hormone. The ligand of the immunotoxin directs the molecule to the surface of the tumor cell, where the toxin enters the cell to kill the cell. Most toxins work by inactivating the cell ribosomes, thereby stopping protein synthesis in the cell. See, e.g., Oncology, "Immunotoxin Therapy of Cancer", May 1993.
While effective in some cases, several problems have been recognized with immunotoxin therapy, making it clear that immunotoxin therapy is not, at least so far, the "silver bullet" for cancer treatment that it was once hoped to be.
One problem with immunotoxin therapy is that the large size of the immunotoxin molecules and the poor vasculature of most tumors leads to a high intravascular drug concentration but a low drug concentration in the tumor interstitia. Consequently, toxicities to accessible normal tissues is high, while efficacy is poor. For example, immunotoxins have been found to react with neural and hepatic tissue antigens and produce serious, and sometimes fatal, toxicities.
Another problem with immunotoxins is that they are significantly immunogenic, generating humoral immune responses to the molecule. The resulting immune complexes of antibody-immunotoxin reduce the effective level of immunotoxin systemically by, for example, inhibiting the internalization of the immunotoxin into the tumor cell.
A second known method for treating tumors with a toxin involves the intravenous treatment of a tumor using a sub-lethal dose of the toxin. This treatment, about which there is only one report known to the present inventors, demonstrated an antitumor effect of the toxin in human clinical trials, but the patients had adverse side effects at high doses. In addition, since toxins are notably immunogenic, the patients mounted an immune response to the toxin which eventually abrogated any effect of the treatment.
Most notably, the above report on the clinical experiment concluded that intravenous treatment of a tumor with a toxin suffered from a problem of having a limited duration of effective therapy. The report concluded that the therapy becomes ineffective when antibody titers to the toxin in the patient reach a concentration sufficient to counteract or abolish the antitumor effect of the toxin. See Fodstad et al., Cancer Research, "Phase 1 study of the Plant Protein Ricin", Vol. 44, pp. 862-865 (February 1984).